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Am J Physiol Heart Circ Physiol 278: H412-H419, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 2, H412-H419, February 2000

Expression of the beta  (slow)-isoform of MHC in the adult mouse heart causes dominant-negative functional effects

Jil C. Tardiff1, Timothy E. Hewett2, Stephen M. Factor1, Karen L. Vikstrom3, Jeffrey Robbins2, and Leslie A. Leinwand4

1 Department of Medicine, Albert Einstein College of Medicine, Bronx 10461; 3 State University of New York, Health Science Center, Syracuse 13210;2  Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children's Hospital Research Foundation, Cincinnati, Ohio 45229; and 4 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309

alpha - and beta -myosin heavy chain (MHC), the two MHC isoforms expressed in the mammalian heart, differ quantitatively in their enzymatic activities. The MHC composition of the heart can change dramatically in response to numerous stimuli, leading to the hypothesis that changes in cardiac function can be caused by myosin isoform shifts. However, this hypothesis has remained unproven because the stimuli used to generate these shifts are complex and accompanied by many additional physiological changes, including alterations in cardiac mass and geometry. Adult mouse ventricles normally express only alpha -MHC (the faster motor). To determine whether genetic alteration of the MHC isoform composition in the adult mouse heart would result in changes in cardiac chamber mass and contractility, we established transgenic mouse lines that express a Myc-tagged beta -MHC molecule (the slower motor) in adult ventricular tissue, one of which expreses 12% of its myosin as the transgene. There is no evidence of hypertrophy, induction of hypertrophic markers, and no histopathology. Myofibrillar Ca2+-activated ATPase activity is decreased by 23%, and Langendorff preparations demonstrate a significant 15% decrease in systolic function in transgenic hearts. These results suggest that even small shifts in the myosin isoform composition of the myocardium can result in physiologically significant changes in cardiac contractility and could be relevant to cardiovascular disease.

myosin heavy chain; contractility; transgenic


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